JP6360007B2 - Method for producing drug-containing particles - Google Patents

Description

  The present invention relates to a method for producing drug-containing particles, a drug-containing particle, a pharmaceutical composition, and an orally disintegrating tablet.

  Some drugs used in pharmaceuticals have an unpleasant odor. For example, drugs having a (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group (hereinafter referred to as “medoxomil group”) such as olmesartan medoxomil, azilsartan medoxomil, faropenem medoxomil, lenampicillin and the like. Is known to exhibit an unpleasant odor.

  On the other hand, the development of orally disintegrating tablets that can be taken without water is being promoted as an easier-to-take formulation to improve compliance, such as elderly patients, patients who have difficulty swallowing, and patients whose water intake is restricted. Yes. Orally disintegrating tablets are oral preparations that disintegrate rapidly in the oral cavity after being taken. Therefore, when a drug that exhibits an unpleasant odor is used as the dosage form of an orally disintegrating tablet, the technology reduces the odor derived from the drug. Is particularly important.

  Conventionally, various techniques such as a technique using sugar coating or film coating, a technique using a component that adsorbs a substance causing odor, and the like have been proposed as techniques for reducing odors derived from drugs.

For example, Patent Document 1 discloses a film coating preparation containing olmesartan medoxomil in the formulation and one or more compounds selected from polyvinyl alcohol and a vinyl alcohol copolymer in the film layer. Has been.
Patent Document 2 discloses a pharmaceutical composition containing olmesartan medoxomil in the formulation and one or more compounds selected from polyvinyl alcohol and vinyl alcohol copolymers in the coating. .
Patent Document 3 discloses a film coating preparation containing olmesartan medoxomil in the formulation and dextrose in the film layer.
Patent Document 4 discloses a film coating preparation containing olmesartan medoxomil in the formulation and sodium carboxymethylcellulose in the film layer.
Patent Documents 5 and 6 disclose pharmaceutical compositions containing a drug having a medoxomil group as an active ingredient and cyclodextrin as an additive.
Patent Document 7 discloses that by mixing an odor adsorbent with a packaging material for packaging tablets containing olmesartan medoxomil, the odor when the preparation is taken out from the package can be reduced.

International Publication No. 2009/057569 Japanese Patent No. 5241511 Japanese Patent No. 497579 Japanese Patent No. 5000491 International Publication No. 2010/018777 Japanese Patent Laying-Open No. 2015-61828 Japanese Patent No. 5241503

The odor derived from the drug can be suppressed by sugar coating or film coating technology as disclosed in Patent Documents 1 to 4. However, in the sugar coating technology, the dosage may be deteriorated due to an increase in the formulation. Moreover, according to the technique of the film coating as disclosed in Patent Documents 1 to 4, not only the process becomes complicated, but in the case of a dosage form such as an orally disintegrating tablet, May significantly delay disintegration.
In the techniques disclosed in Patent Documents 5 and 6, in order to sufficiently suppress odor, it is necessary to blend cyclodextrin in the same amount or more as the drug. Therefore, in the case of solid preparations such as orally disintegrating tablets, the dosage may be deteriorated due to the increase in the preparation.
In the technique disclosed in Patent Document 7, a special packaging material is used to reduce the odor when the preparation is taken out from the package. However, in oral preparations such as orally disintegrating tablets, the package is not used. It may be stored or prescribed, and in such a case, the odor cannot be suppressed.

  The present invention has been made in view of the circumstances as described above, and a method for producing drug-containing particles capable of obtaining drug-containing particles with suppressed odor derived from a drug having a medoxomil group, It is an object of the present invention to provide a drug-containing particle to be obtained, a pharmaceutical composition containing the drug-containing particle, and an orally disintegrating tablet.

Specific means for solving the above problems include the following embodiments.
<1> A core particle (A), a drug (B) coated with the core particle (A), having a medoxomil group, a melting point of 50 ° C. to 100 ° C., an HLB value of 6 or less, and carbon A method for producing drug-containing particles comprising a melt granulation step of obtaining drug-containing particles having a coating layer containing a compound (C) having an aliphatic hydrocarbon chain having a number of 12 or more by melt granulation.
<2> In the melt granulation step, at least the core particle (A), the drug (B) having a medoxomil group, and the component containing the compound (C) are heated in a state of being heated above the melting point of the compound (C). <1> The production method according to <1>, wherein granulation is performed using at least one means selected from means and stirring means.
<3> The production method according to <1> or <2>, wherein the core particle (A) contains at least one selected from D-mannitol and crystalline cellulose.
<4> The production method according to any one of <1> to <3>, wherein the drug (B) having a medoxomil group has an average particle size of 20 μm or less.
<5> The production method according to any one of <1> to <4>, wherein the coating layer further includes a disintegrant (D).

<6> The production method according to <5>, wherein the disintegrant (D) contains at least one selected from crospovidone and carmellose calcium.
<7> The production method according to any one of <1> to <6>, wherein the compound (C) is at least one selected from a glycerin fatty acid ester and a sucrose fatty acid ester.
<8> The production method according to any one of <1> to <7>, wherein the compound (C) is at least one selected from glyceryl monostearate and sucrose stearate.
<9> The production method according to any one of <1> to <8>, wherein the drug (B) having a medoxomil group is olmesartan medoxomil.
<10> In the melt granulation step, any one of <1> to <9>, in which 20 parts by mass to 150 parts by mass of the compound (C) is used with respect to 100 parts by mass of the drug (B) having a medoxomil group. The manufacturing method as described in.

<11> Drug-containing particles obtained by the production method according to any one of <1> to <10>.
<12> A pharmaceutical composition comprising the drug-containing particles according to <11>.
<13> The pharmaceutical composition according to <12>, wherein the dosage form is a tablet, capsule, powder, or granule.
<14> An orally disintegrating tablet comprising the drug-containing particles according to <11>.

  According to the present invention, a method for producing drug-containing particles capable of obtaining drug-containing particles with suppressed odor derived from a drug having a medoxomil group, a drug-containing particle obtained by this production method, and this drug-containing particle Pharmaceutical compositions and orally disintegrating tablets can be provided.

It is a graph which shows the measurement result of the diacetyl area using the gas chromatography implemented about the medicine containing particle | grains obtained by the manufacturing method of Example 1 and Comparative Examples 1-3.

  Hereinafter, specific embodiments of the present invention will be described in detail. However, the present invention is not limited to the following embodiments, and may be implemented with appropriate modifications within the scope of the object of the present invention. can do.

In the present specification, a numerical range indicated using “to” means a range including the numerical values described before and after “to” as a minimum value and a maximum value, respectively.
In this specification, the amount of each component in the drug-containing particles, the pharmaceutical composition, and the orally disintegrating tablet is such that there are a plurality of substances corresponding to each component in the drug-containing particles, the pharmaceutical composition, and the orally disintegrating tablet. When the species is present, it means the total amount of the plurality of types of substances present in the drug-containing particles, the pharmaceutical composition, and the orally disintegrating tablet unless otherwise specified.

In the present specification, the “average particle diameter” refers to a volume average particle diameter (Mv), which is a value measured using a laser diffraction / scattering particle size distribution measuring apparatus. As the measuring device, for example, LS 13 320 (product name) manufactured by Beckman Coulter can be preferably used. However, the measuring device is not limited to this.
In the present specification, the term “layer” includes not only a configuration covering the entire coating target but also a configuration covering a part of the coating target.

  In this specification, the term “process” is not limited to an independent process, and is included in the term if the intended purpose of the process is achieved even when it cannot be clearly distinguished from other processes. .

[Method for producing drug-containing particles]
The method for producing drug-containing particles of the present embodiment (hereinafter, also simply referred to as “manufacturing method”) includes a core particle (A), a drug covering the core particle (A) and having a medoxomil group (B), and Compound (C) having a melting point of 50 ° C. to 100 ° C., an HLB (Hydrophile-Lipophile Balance) value of 6 or less, and an aliphatic hydrocarbon chain having 12 or more carbon atoms (hereinafter simply referred to as “compound ( C) also includes a coating layer including a melting granulation step of obtaining drug-containing particles having melt coating by granulation.
The production method of the present embodiment may include other steps other than the melt granulation step as necessary, as long as the effects of the present invention are not impaired.

When a drug having a medoxomil group is decomposed by hydrolysis or the like, 2,3-butanedione (hereinafter referred to as “diacetyl”) having an unpleasant odor is generated. An unpleasant odor of the drug is not preferable because it deteriorates the dose.
According to the production method of the present embodiment, drug-containing particles with suppressed odor derived from a drug having a medoxomil group can be obtained.
Although the reason why the manufacturing method of this embodiment can achieve such an effect is not clear, the present inventors presume as follows.

  In the production method of the present embodiment, the core particle (A), the core particle (A), the drug (B) having a medoxomil group, the melting point is 50 ° C. to 100 ° C., and the HLB value is 6 or less. And a drug (B) having a medoxomil group by producing drug-containing particles having a coating layer containing a compound (C) having an aliphatic hydrocarbon chain having 12 or more carbon atoms by melt granulation Is considered to be coated with the compound (C). The drug (B) having a medoxomil group is coated with the compound (C), so that it is hardly affected by humidity in the storage environment and the like, and as a result of suppressing decomposition, generation of diacetyl that exhibits an unpleasant odor is suppressed. It is thought that it is done.

  In the production method of the present embodiment, when a drug exhibiting a bitter taste such as olmesartan medoxomil is used as the drug (B) having a medoxomil group, drug-containing particles not only having an unpleasant odor but also suppressing the bitter taste are used. Can be obtained.

  In the production method of the present embodiment, the drug-containing particles containing the drug (B) having a medoxomil group are produced by melt granulation, so that conventional granulation methods (jet fluidized bed granulation, fluidized bed granulation, The suppression of odor derived from the drug (B) having a medoxomil group can be realized with a smaller number of steps compared to a granulating method such as rolling fluidized bed granulation).

  Hereinafter, each process in the manufacturing method of this embodiment is demonstrated in detail. Details of components used in each step will be described later.

<Melt granulation process>
In the melt granulation step, the core particle (A), the core particle (A), the drug (B) having a medoxomil group, the melting point is 50 ° C. to 100 ° C., the HLB value is 6 or less, And it is the process of obtaining the drug containing particle | grains which have a coating layer containing the compound (C) which has a C12 or more aliphatic hydrocarbon chain | strand, and are obtained by melt granulation.
In the melt granulation step, it is considered that the surface of the core particle (A) can obtain drug-containing particles coated with a coating layer containing a drug (B) having a medoxomil group coated with the compound (C). .

In the melt granulation step, at least the core particles (A), the drug (B) having a medoxomil group, and the compound (C) -containing component are heated to the melting point of the compound (C) or higher, and the rolling means and stirring are performed. It is preferable to perform granulation using at least one means selected from the means.
At least one means selected from the rolling means and the stirring means for the component containing the core particle (A), the drug (B) having a medoxomil group and the compound (C) in a state heated to the melting point of the compound (C) or higher. When the granule is used for granulation, the drug (B) having a medoxomil group is satisfactorily covered with the melted compound (C), so that drug-containing particles with a more suppressed odor can be obtained.

In the melt granulation step, from the viewpoint of melting and granulating the compound (C), at least a component containing the core particle (A), the drug (B) having a medoxomil group and the compound (C) is added to the compound (C). It is preferable to perform granulation in the state heated to the melting point or higher.
The granulated product when granulated or the temperature in the vicinity of the granulated product (that is, the granulation temperature) is selected from the viewpoints of the suppression of decomposition of the drug (B) having a medoxomil group and the energy required for heating. The temperature is preferably not lower than the melting point and not higher than 50 ° C. above the melting point, preferably not lower than the melting point of the compound (C) and not higher than 40 ° C. higher than the melting point.

  The temperature not lower than the melting point of the compound (C) may be achieved when the core particles (A), the drug (B) having a medoxomil group, and the compound (C) are granulated. For example, you may granulate the component containing a core particle (A), the drug (B) which has a medoxomil group, a compound (C), etc., heating it more than melting | fusing point of a compound (C).

As a method of heating the component containing the core particle (A), the drug having a medoxomil group (B), the compound (C), etc. to the melting point of the compound (C) or more, there is no use for heating and cooling such as a mantle heater. Examples include a method of heating a container charged with core particles (A), a drug having a medoxomil group (B), a compound (C), and the like using a bath (jacket). Moreover, when using a granulation apparatus provided with both a heating mechanism and a granulation mechanism, granulation using means, such as an outer bath (jacket) for heating and cooling, supply of heating gas, and microwave heating, is carried out. The compound (C) in the apparatus may be heated to the melting point or higher to granulate components including the core particles (A), the drug (B) having a medoxomil group, the compound (C) and the like.
Further, when granulating, the order in which the core particles (A), the drug (B) having a medoxomil group, and the compound (C) are charged into the container is not particularly limited. For example, the particles may be charged all at once into the container. In addition, from the viewpoint of uniformly coating the surface of the core particle (A) with the drug (B) having a medoxomil group and the compound (C), the drug having the medoxomil group (B) ) And compound (C) may be gradually added.

In the melt granulation step, at least the core particles (A), the drug (B) having a medoxomil group, and the compound (C) are granulated using at least one means selected from rolling means and stirring means. It is preferable to do.
Here, “rolling” means giving a rolling motion to the raw material powder of the primary particles by the action of the stirring blade in the granulation vessel, and “stirring” means in the granulation vessel. This means that shearing, rolling, compaction, etc. are given by the action of the stirring blade.
As granulation means in the melt granulation step, at least one of rolling action and stirring action is an apparatus that works on the core particles (A), the drug having a medoxomil group (B), the compound (C) and the like ( That is, there is no particular limitation as long as it is a granulating device.
Examples of the granulator include known granulators such as a mortar and pestle, a high-speed stirring granulator, a rolling granulator, and a rolling fluidized bed granulator.

  As a granulator, a rolling fluidized bed granulator (model name: FD-MP-01, Pauleck Co., Ltd.) equipped with a rolling fluidized unit (model name: MP) whose bottom of the fluidized bed rotates, heating and stirring Examples thereof include a high-speed stirring granulator (VG series, Paulek Co., Ltd.) having a mechanism.

The rotor rotation speed of the granulating apparatus is not particularly limited, and can be appropriately set according to the size of the rotor, the composition of the granulated material, and the like.
The granulation time is not particularly limited, and can be appropriately set according to the type of granulation equipment, the granulation scale, the composition of the granulated material, and the like. For example, in the case of a granulation scale that obtains a granulated product of 1 kg to 10 kg using a granulator, the granulation time is usually 10 minutes to 30 minutes.

  The amount of the core particle (A) used is not particularly limited. For example, the surface of the core particle (A) is coated with the drug (B) having a medoxomil group and the compound (C), and the drug having a medoxomil group (B ) And the compound (C), from the viewpoint of suppressing the by-generation of the drug-containing particles, it is preferably 20 to 90 parts by mass with respect to 100 parts by mass in total of the components constituting the drug-containing particles. It is more preferable that it is 30 mass parts-80 mass parts.

The use amount of the drug (B) having a medoxomil group can be appropriately set in consideration of the type of drug, the daily dose, and the like.
The amount of the drug (B) having a medoxomil group is preferably, for example, 10 parts by mass to 75 parts by mass, and 15 parts by mass to 50 parts by mass with respect to 100 parts by mass in total of the components constituting the drug-containing particles. More preferably, it is a part.

  The amount of the compound (C) used is, for example, preferably 1 part by mass to 50 parts by mass with respect to 100 parts by mass in total of the components constituting the drug-containing particles, and 5 parts by mass to 45 parts by mass. Is more preferable, and it is still more preferable that they are 5 mass parts-40 mass parts.

  The amount of the compound (C) used is 20 to 150 parts by mass with respect to 100 parts by mass of the drug (B) having a medoxomil group from the viewpoint of suppressing the odor derived from the drug (B) having a medoxomil group. It is preferable that it is 30 mass parts-140 mass parts, and it is still more preferable that it is 40 mass parts-130 mass parts.

In the melt granulation step, it is preferable to granulate by including the disintegrant (D) together with the core particles (A), the drug (B) having a medoxomil group, and the compound (C).
By including the disintegrant (D) and granulating, the dissolution property of the drug (B) having a medoxomil group from the drug-containing particles after taking can be improved.
When the disintegrant (D) is used in the melt granulation step, the amount of the disintegrant (D) used may be 1 part by mass to 100 parts by mass with respect to 100 parts by mass of the drug (B) having a medoxomil group. Preferably, it is 2 mass parts-50 mass parts, More preferably, it is 3 mass parts-20 mass parts.

  In the melt granulation step, as long as the effect of the present invention is not impaired, an active ingredient other than the excipient and the drug (B) having a medoxomil group (hereinafter also referred to as “other active ingredient”) as necessary. Other components such as these may be granulated together with the core particles (A), the drug (B) having a medoxomil group, the compound (C) and the like.

  When an excipient is used in the melt granulation step, the amount of the excipient used is preferably, for example, 10 parts by mass to 90 parts by mass with respect to a total of 100 parts by mass of the components constituting the drug-containing particles. 20 parts by mass to 80 parts by mass is more preferable, and 30 parts by mass to 70 parts by mass is more preferable.

  When other active ingredients are used in the melt granulation step, the amount of other active ingredients used can be appropriately set in consideration of, for example, the type of other active ingredients, the daily dose, and the like.

<Other processes>
The production method of the present embodiment may include other steps other than the melt granulation step as necessary, as long as the effects of the present invention are not impaired.
Other processes include a coating process in which the surface of the granulated product granulated in the melt granulation process is coated with a film having an elution control ability (so-called elution control layer), and granulation granulated in the melt granulation process. Examples thereof include a sizing step for adjusting the particle diameter of the product.

<Coating process>
The coating step is a step of coating the surface of the granulated product granulated in the melt granulation step with a film having a dissolution control ability (a so-called dissolution control layer).
In the coating step, the surface of the granulated product granulated in the melt granulation step is coated with an elution control layer, whereby the time-release property or sustained release property can be imparted to the drug-containing particles. The embodiment in which the drug-containing particles have an elution control layer is a particularly preferable embodiment when the drug-containing particles are used as fine granules of an orally disintegrating tablet.

  Specifically, as a film forming the elution control layer, a gastric film and an enteric film that release a drug at a target site by changing the solubility according to the pH of the liquid to be contacted, a certain period of time Water-soluble membrane that dissolves in water but prevents drug release during that time, water-insoluble membrane that releases drug only slowly from between membranes due to low water solubility or water insolubility, membrane that combines these functions Etc.

The membrane component forming the elution control layer is not particularly limited, and a membrane component known in the pharmaceutical field can be used.
As a method of covering the surface of the granulated product granulated in the melt granulation step with the elution control layer, a general granulation method can be employed. For example, an elution control layer spray solution in which a film component forming the elution control layer is dissolved in a solvent may be prepared and sprayed onto a granulated product to be coated.
The spraying speed, spraying time, liquid temperature, drying conditions after spraying, etc. of the elution control layer spray liquid are not particularly limited, and can be appropriately set according to the composition, viscosity, etc. of the spray liquid.

<< Sizing process >>
The sizing step is a step of adjusting the particle size of the granulated product granulated in the melt granulation step.
When the manufacturing method of this embodiment includes the coating step described above, the sizing step is preferably performed after the coating step.
Examples of the method for adjusting the particle size of the granulated product include sieving with a sieve and sizing with a granulator.

  Hereinafter, components and the like used in the manufacturing method of the present embodiment will be described in detail.

<Nuclear particle (A)>
The core particle (A) is a particle that can serve as a base material for producing drug-containing particles.
The component constituting the core particle (A) is not particularly limited as long as it is a pharmacologically acceptable component.
Examples of the component constituting the core particle (A) include D-mannitol, lactose, crystalline cellulose, purified white sugar, magnesium aluminate metasilicate, anhydrous calcium hydrogen phosphate, calcium silicate, magnesium oxide, magnesium carbonate, and the like.
Among these, the core particles (A) preferably contain at least one selected from D-mannitol and crystalline cellulose from the viewpoints of the sphericity of the particles, strength, and drug stability.
As the core particle (A), the raw powder itself of the above components may be used, or a granulated product of the above raw material of the above components may be used.

The average particle diameter of the core particles (A) is preferably, for example, 50 μm to 350 μm, and more preferably 100 μm to 300 μm.
As the average particle diameter of the core particles (A) approaches the upper limit value of the above preferred range, a uniform granulated product can be obtained, and the average particle diameter of the core particles (A) becomes the lower limit value of the above preferred range. The closer it is, the better the feel of the drug-containing particles.

A commercial item may be used as a core particle (A).
Examples of commercially available core particles (A) include SELFIA (registered trademark) CP-203 (trade name, crystalline cellulose (grains), Asahi Kasei Chemicals Corporation), Nonparel (registered trademark) -108 (trade name, D -Mannitol, Freund Sangyo Co., Ltd., Nonparel (registered trademark) -105 (trade name, lactose and crystalline cellulose, Freund Sangyo Co., Ltd.), Florite RE (trade name, calcium silicate, Eisai Food Chemical Co., Ltd.) )), PCS (registered trademark) (trade name, partially alpha starch, Asahi Kasei Chemicals Co., Ltd.), Sukurene (registered trademark) SR60 / 80 (trade name, refined white sugar, Shimizu Minato Sugar Co., Ltd.), etc. .

<Drug having medoxomil group (B)>
Examples of the drug (B) having a medoxomil group include olmesartan medoxomil, azilsartan medoxomil, faropenem medoxomil, lenampicillin and the like.
Olmesartan medoxomil and azilsartan medoxomil are drugs known as antihypertensive drugs and the like, and faropenem medoxomil and lenampicillin are drugs known as antibiotics and the like.
Among these, as the drug (B) having a medoxomil group, olmesartan medoxomil is preferable.
Olmesartan medoxomil is known as a drug having a bitter taste as well as an unpleasant odor by being decomposed by hydrolysis or the like.
In the production method of the present embodiment, as a drug (B) having a medoxomil group, by using a drug exhibiting a bitter taste such as olmesartan medoxomil, a drug containing both unpleasant odor and bitterness derived from olmesartan medoxomil is suppressed. There is an advantageous effect that particles can be obtained.

The drug (B) having a medoxomil group may be a synthetic product or a commercially available product.
For example, olmesartan medoxomil can be produced according to the method described in Japanese Patent No. 2082519.

  In the melt granulation step, the drug (B) having a medoxomil group may be used alone or in combination of two or more.

The drug (B) having a medoxomil group usually has a granular form.
The average particle size of the drug (B) having a medoxomil group is preferably sufficiently smaller than the average particle size of the core particle for coating the core particle (A), and is preferably 20 μm or less, for example. More preferably, it is 10 μm or less.
The average particle size of the drug (B) having a medoxomil group is preferably 1 μm or more.

<Compound (C)>
The compound (C) is a compound having an aliphatic hydrocarbon chain having a melting point of 50 ° C. to 100 ° C., an HLB value of 6 or less, and a carbon number of 12 or more.
In the melt granulation step, the compound (C) acts as a binder for forming a coating layer containing a drug (B) having a medoxomil group, a coating agent for the drug (B) having a medoxomil group, and the like.

The melting point of the compound (C) is 50 ° C to 100 ° C, preferably 50 ° C to 95 ° C, and more preferably 50 ° C to 90 ° C.
When the melting point of the compound (C) is 50 ° C. or higher, the stability during storage of the drug-containing particles is hardly impaired. Moreover, when the melting point of the compound (C) is 50 ° C. or higher, the storage stability of the obtained drug-containing particles at a high temperature of about 40 ° C. can be obtained.
When the melting point of the compound (C) is 100 ° C. or less, energy required for heating in the melt granulation step can be suppressed. Moreover, when the melting point of the compound (C) is 100 ° C. or lower, the thermal decomposition of the drug (B) having a medoxomil group can be suppressed.

The HLB value of the compound (C) is 6 or less, preferably 5 or less, and more preferably 4 or less.
When the HLB value of the compound (C) is 6 or less, the odor derived from the drug (B) having a medoxomil group can be suppressed. Moreover, when the drug (B) having a medoxomil group is olmesartan medoxomil, the bitterness derived from olmesartan medoxomil can also be suppressed.
Further, the HLB value of the compound (C) is preferably 0.5 or more, and preferably 1 or more, from the viewpoint of the dissolution property of the drug (B) having a medoxomil group from the drug-containing particles after taking. More preferred.

As the HLB value of the compound (C) in the present specification, a commercially available product is used as the compound (C), and the HLB value of the commercially available product is clearly shown in a literature such as a catalog of the commercially available product. The value shown in the literature such as a catalog is used for.
When the compound (C) is not a commercially available product, or even if it is a commercially available product, the HLB value is not clearly shown in a literature such as a catalog, the HLB value of the compound (C) in this specification is The value obtained by the Davies method is adopted. In the Davies method, the HLB value is calculated according to the following Davies formula.
HLB value = 7 + (total number of hydrophilic groups) − (total number of lipophilic groups)

The number of carbon atoms of the aliphatic hydrocarbon chain of the compound (C) is 12 or more, preferably 15 or more, and more preferably 18 or more.
Moreover, it is preferable that carbon number of the aliphatic hydrocarbon chain which a compound (C) has is 22 or less.
When the aliphatic hydrocarbon chain of the compound (C) has 12 or more carbon atoms, the melting point is increased and drug-containing particles having excellent storage stability can be obtained.

  From the viewpoint of drug elution from the drug-containing particles after taking, the compound (C) preferably has at least one partial structure selected from an ester bond, a carboxy group, and a hydroxyl group.

Examples of the compound (C) include glycerin fatty acid esters (including hardened oils such as hardened castor oil and hard rapeseed oil), fatty acids such as sucrose fatty acid esters, stearic acid and palmitic acid, aliphatic alcohols such as stearyl alcohol and palmitoyl alcohol, and carnauba wax. And the like.
Among these, as a compound (C), it is preferable that it is at least 1 sort (s) chosen from glycerol fatty acid ester and sucrose fatty acid ester, and it is at least 1 sort (s) chosen from glycerol mono fatty acid ester and sucrose fatty acid ester. More preferred.

Examples of the glycerin fatty acid ester include glyceryl monostearate, glyceryl monobehenate, and glyceryl monolaurate, and glyceryl monostearate is preferable from the viewpoint of oral administration.
Examples of the sucrose fatty acid ester include sucrose stearate ester, sucrose palmitate ester, sucrose oleate ester, sucrose laurate ester, sucrose behenate ester, etc., from the viewpoint of oral administration results and melting point, Sucrose stearate is preferred.

  Examples of the compound (C) include suppression of odor derived from a drug (B) having a medoxomil group, suppression of bitterness when the drug (B) having a medoxomil group is a drug exhibiting a bitter taste such as olmesartan medoxomil, And at least one selected from glycerin fatty acid esters and sucrose fatty acid esters having an HLB value in the range of 0.5 to 6 from the viewpoint of elution of the drug (B) having a medoxomil group from the drug-containing particles after taking It is preferable that

  In the melt granulation step, the compound (C) may be used alone or in combination of two or more.

Compound (C) is also available as a commercial product.
Examples of commercially available products of the glycerin fatty acid ester which is the compound (C) include P-100 (trade name, glyceryl monostearate, HLB value: about 4.3 (catalog value), melting point: 63 ° C. to 83 ° C. (catalog Value), carbon number of aliphatic hydrocarbon chain: 18, Riken Vitamin Co., Ltd., Riquemar (registered trademark) B-100 (trade name, glyceryl monobehenate, HLB value: 4.2 (catalog value), melting point: 75 ° C to 85 ° C (catalog value), carbon number of aliphatic hydrocarbon chain: 22, Riken Vitamin Co., Ltd., Poem (registered trademark) M-300 (trade name, monolaurate glycerin, HLB value: 5.4) (Catalog value), melting point: about 57 ° C. (catalog value), aliphatic hydrocarbon chain carbon number: 12, Riken Vitamin Co., Ltd.) and the like.

  As an example of a commercial product of the hardened oil which is the compound (C), Labriwax (registered trademark) -101 (trade name, hardened castor oil, HLB value: -5.8 (calculated by the Davies method), melting point: 86 ° C ( Catalog value), number of carbons of aliphatic hydrocarbon chain: Mainly 18, Freund Sangyo Co., Ltd., Loveli wax (registered trademark) -103 (trade name, hardened rapeseed oil, HLB value: -11.5 (Davies method) Calculation), melting point: 69 ° C. (catalog value), aliphatic hydrocarbon chain carbon number: mainly 18, Freund Sangyo Co., Ltd.) and the like.

As an example of a commercial item of sucrose fatty acid ester which is compound (C), Surf Hope (registered trademark) SE PHARMA J-1803F (trade name, sucrose stearate ester, HLB value: about 3 (catalog value), melting point : 60.5 ° C. (catalog value), carbon number of aliphatic hydrocarbon chain: 18, Mitsubishi Chemical Foods Co., Ltd., Ryoto (registered trademark) sugar ester S-070 (trade name, sucrose stearate, HLB Value: about 0, melting point: 65.7 ° C. (catalog value), carbon number of aliphatic hydrocarbon chain: 18, Mitsubishi Chemical Foods Co., Ltd., Ryoto (registered trademark) Sugar ester S-170 (trade name, Sho Sugar stearate, HLB value: about 1 (catalog value), melting point: 68.3 ° C. (catalog value), carbon number of aliphatic hydrocarbon chain: 18, Mitsubishi Chemical Foods) Ryoto® sugar ester S-370F (trade name, sucrose stearate ester, HLB value: about 3 (catalog value), melting point: 60.5 ° C. (catalog value), carbon number of aliphatic hydrocarbon chain: 18, Mitsubishi Chemical Foods Co., Ltd.).
In the present specification, the HLB value of “about 0” is described as 1 or less in the catalog, and the HLB means 0 or more and less than 0.5.

As an example of a commercial item of fatty acid which is compound (C), Steadic Acid, Powder, NF-GenAR (trade name, stearic acid, HLB value: 1.0 (calculated by Davies method), melting point: 53 ° C. to 59 ° C. (Catalog value), Aliphatic hydrocarbon chain carbon number: 18, Avantor Performance Materials, Inc.).
As an example of a commercial product of the aliphatic alcohol which is the compound (C), NIKKOL (registered trademark) deodorized stearyl alcohol (trade name, stearyl alcohol, HLB value: about 1 (calculated by the Davies method), melting point: 59 ° C. to 60 ° C. ° C (catalog value), carbon number of aliphatic hydrocarbon chain: 18, Nikko Chemicals Co., Ltd.) and the like.

  Examples of commercially available waxes of compound (C) include polishing wax-105 (trade name, Carnauba wax, HLB value: -16.7 (calculated by the Davies method), melting point: 80 ° C. to 86 ° C., aliphatic carbonization. Examples of the carbon number of the hydrogen chain: 24-28, Freund Sangyo Co., Ltd.).

<Disintegrant (D)>
The disintegrant is not particularly limited as long as it is a component that can function as a disintegrant and is pharmacologically acceptable, and a known disintegrant can be used.
Examples of the disintegrant include starch (corn starch, potato starch, etc.), pregelatinized starch (including partially pregelatinized starch), starch such as sodium starch glycolate, hydroxypropyl starch, and derivatives thereof, carmellose, carmellose calcium , Carmellose sodium, croscarmellose sodium, hydroxypropylcellulose (including low-substituted hydroxypropylcellulose), crystalline cellulose, crystalline cellulose / carmellose sodium, methylcellulose, cellulose such as hipmelose and their derivatives, and crospovidone And povidone derivatives.
Among these, the disintegrant preferably contains at least one selected from crospovidone and carmellose calcium from the viewpoint of drug elution from the drug-containing particles after taking.
In the melt granulation step, one type of disintegrant may be used alone, or two or more types may be used in combination.

  Although the average particle diameter of the disintegrant is not particularly limited, for example, from the viewpoint of covering the surface of the core particle (A), it is preferably 1 μm to 100 μm, and more preferably 10 μm to 70 μm.

<Excipient>
The excipient is not particularly limited as long as it is a component that can function as an excipient and is pharmacologically acceptable, and a known excipient can be used.
The excipient may be an organic excipient or an inorganic excipient.
Examples of the organic excipient include D-mannitol, sorbitol, erythritol, lactose, purified sucrose, crystalline cellulose, ethyl cellulose and the like.
Examples of the inorganic excipient include magnesium aluminate metasilicate, magnesium oxide, magnesium carbonate, magnesium phosphate, calcium silicate, anhydrous calcium phosphate, hydrous magnesium silicate (ie, talc) and the like.
When using an excipient | filler in a melt granulation process, an excipient | filler may be used individually by 1 type and may be used in combination of 2 or more type.

<Other active ingredients>
Examples of other active ingredients include antihypertensive drugs, antidiabetic drugs, hyperlipidemia drugs, hyperuricemia drugs, and the like.
Examples of antihypertensive drugs include calcium antagonists and diuretics.
Examples of calcium antagonists include amlodipine, nifedipine, nicardipine, benidipine, varnidipine, nitrendipine, nisoldipine, azelnidipine, manidipine, efonidipine, cilnidipine, alanidipine, felodipine, nimodipine, clevidipine, lacidipine, lercanidipine and the like.
Examples of diuretics include furosemide, torasemide, azosemide, piretanide, hydrochlorothiazide, trichlormethiazide, indapamide, chlorthalidone, triamterene, spironolactone, potassium canrenoate, eplerenone, acetazolamide, carperitide, tolvaptan and the like.
When other active ingredients are used in the melt granulation step, the other active ingredients may be used alone or in combination of two or more.

[Drug-containing particles]
The drug-containing particles of the present embodiment are obtained by the manufacturing method of the present embodiment described above.
The drug-containing particles of the present embodiment are coated with the core particles (A), the core particles (A), the drug (B) having a medoxomil group, the melting point is 50 ° C. to 100 ° C., and the HLB value is 6 or less. And a coating layer containing the compound (C) having an aliphatic hydrocarbon chain having 12 or more carbon atoms.
Although the drug-containing particles of the present embodiment contain a drug having a medoxomil group, the odor derived from the drug having a medoxomil group is suppressed, and the difficulty in taking due to an unpleasant odor is low. In addition, when the drug-containing particles of the present embodiment include a drug exhibiting a bitter taste such as olmesartan medoxomil as a drug having a medoxomil group, since the bitter taste is suppressed, the difficulty of taking the bitter taste is low.

  For details of the core particles (A) contained in the drug-containing particles of the present embodiment, the drug (B) having a medoxomil group, and optional components such as the compound (C), the disintegrant (D), and the additive for formulation, Since it was mentioned above, description is abbreviate | omitted here.

  The content ratio of the core particles (A) in the drug-containing particles is preferably, for example, 20% by mass to 90% by mass, and preferably 30% by mass to 80% by mass with respect to the total mass of the drug-containing particles. More preferred.

The content ratio of the drug (B) having a medoxomil group in the drug-containing particles can be appropriately set in consideration of the type of drug, the daily dose, and the like.
The content ratio of the drug (B) having a medoxomil group in the drug-containing particles is, for example, 5% by mass or more based on the total mass of the drug-containing particles from the viewpoint of the size of the tablet in the case of making a tablet. Preferably, it is 10 mass% or more.
Further, the content ratio of the drug (B) having a medoxomil group in the drug-containing particles is, for example, 95% by mass or less based on the total mass of the drug-containing particles from the viewpoint of uniform coating on the surface of the core particles (A). It is preferable that it is 90 mass% or less.

The content ratio of the compound (C) in the drug-containing particles is, for example, suppression of odor derived from the drug (B) having a medoxomil group, and a drug in which the drug (B) having a medoxomil group exhibits a bitter taste like olmesartan medoxomil From the viewpoint of suppressing the bitter taste in the case of the above, it is preferably 1% by mass or more, more preferably 5% by mass or more with respect to the total mass of the drug-containing particles.
In addition, the content ratio of the compound (C) in the drug-containing particles is preferably 50% by mass or less, and 40% by mass or less with respect to the total mass of the drug-containing particles, for example, from the viewpoint of drug elution. More preferably.

Further, the content of the compound (C) in the drug-containing particles is preferably 20 parts by mass to 150 parts by mass with respect to 100 parts by mass of the drug (B) having a medoxomil group, and 50 parts by mass to 100 parts by mass. It is more preferable that
When the content of the compound (C) in the drug-containing particles is within the above range with respect to 100 parts by mass of the drug (B) having a medoxomil group, an unpleasant odor derived from the drug (B) having a medoxomil group Is more suppressed. In addition, when the drug (B) having a medoxomil group is a drug exhibiting a bitter taste such as olmesartan medoxomil, the bitter taste is further suppressed.

When the drug-containing particles contain the disintegrant (D), the content ratio of the disintegrant (D) in the drug-containing particles is, for example, 1% by mass with respect to the total mass of the drug-containing particles from the viewpoint of drug elution The above is preferable, and 2% by mass or more is more preferable.
The content ratio of the disintegrant (D) in the drug-containing particles is, for example, the suppression of odor derived from the drug (B) having a medoxomil group, and the bitterness that the drug (B) having a medoxomil group is like olmesartan medoxomil. From the viewpoint of suppression of bitterness in the case of a drug exhibiting, the content is preferably 40% by mass or less, more preferably 30% by mass or less, based on the total mass of the drug-containing particles.

When the drug-containing particles contain a disintegrant (D), the drug-containing particles contain 20 parts by mass to 150 parts by mass of the compound (C) with respect to 100 parts by mass of the drug (B) having a medoxomil group, and disintegrate It is preferable that 1 part by mass to 40 parts by mass of the agent (D) is contained, 50 parts by mass to 100 parts by mass of the compound (C), and 2 parts by mass to 30 parts by mass of the disintegrant (D). preferable.
The drug-containing particles contain the drug (B) having a medoxomil group, the compound (C), and the disintegrant (D) in the above proportions, thereby causing an unpleasant odor derived from the drug (B) having a medoxomil group. In the case where the drug (B) having a medoxomil group is a drug exhibiting a bitter taste like olmesartan medoxomil, the bitterness can be further successfully suppressed, and after taking, The drug can be eluted well.

<Average particle size of drug-containing particles>
The average particle size of the drug-containing particles of the present embodiment is preferably, for example, 50 μm to 2000 μm, and more preferably 250 μm to 1500 μm.
When the drug-containing particles of the present embodiment are used as fine granules of an orally disintegrating tablet, the average particle size is preferably 50 μm to 500 μm, more preferably 75 μm to 450 μm, and 100 μm to 400 μm. More preferably.

[Pharmaceutical composition]
The pharmaceutical composition of this embodiment includes the drug-containing particles of this embodiment described above.
The pharmaceutical composition of the present embodiment may contain a pharmacologically acceptable formulation additive in addition to the drug-containing particles of the present embodiment, depending on the dosage form. Examples of the additive for formulation include excipients, disintegrants, lubricants, binders, fluidizing agents and the like.
As for the additive for formulation, one component may perform two or more functions.

An excipient | filler is a component which can contribute to the improvement of the moldability of a pharmaceutical composition.
The excipient is not particularly limited as long as it is a component that can function as an excipient and is pharmacologically acceptable, and a known excipient can be used.
The excipient may be an organic excipient or an inorganic excipient.
Examples of the organic excipient include D-mannitol, sorbitol, erythritol, lactose, purified sucrose, crystalline cellulose, ethyl cellulose, corn starch and the like.
Examples of the inorganic excipient include magnesium aluminate metasilicate, magnesium oxide, magnesium carbonate, magnesium phosphate, calcium silicate, anhydrous calcium phosphate, and the like.

A disintegrant is a component that can contribute to the promotion of disintegration of a pharmaceutical composition.
The disintegrant is not particularly limited as long as it is a component that can function as a disintegrant and is pharmacologically acceptable, and a known disintegrant can be used.
Disintegrants include starch such as corn starch and potato starch, pregelatinized starch, partially pregelatinized starch, starch glycolate, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, crospovidone, low substituted hydroxy Examples include propylcellulose, crystalline cellulose, hydroxypropyl starch and the like.

Lubricants are components that can contribute to improving the manufacturability of pharmaceutical compositions.
The lubricant is not particularly limited as long as it is a component that can function as a lubricant and is pharmacologically acceptable, and a known lubricant can be used.
Examples of the lubricant include sodium stearyl fumarate, magnesium stearate, calcium stearate, aluminum stearate, leucine, talc, and light anhydrous silicic acid.

The binder is a component that can contribute to the improvement of the moldability of the pharmaceutical composition.
The binder is not particularly limited as long as it is a component that can function as a binder and is a pharmacologically acceptable component, and a known binder can be used.
Examples of the binder include hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxyvinyl polymer, sodium carboxymethylcellulose, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, gum arabic, gelatin, pregelatinized starch, pullulan and the like.

The fluidizing agent is a component that can contribute to the improvement of the manufacturability of the pharmaceutical composition.
The fluidizing agent is not particularly limited as long as it is a component that can function as a fluidizing agent and is pharmacologically acceptable, and a known fluidizing agent can be used.
Examples of the fluidizing agent include talc, light anhydrous silicic acid, hydrous silicon dioxide and the like.

The pharmaceutical composition of this embodiment may contain the additive for formulation individually by 1 type, and may contain it in combination of 2 or more type.
The content of the pharmaceutical additive in the pharmaceutical composition can be appropriately set in consideration of the content ratio of the drug-containing particles in the pharmaceutical composition, the particle diameter of the drug-containing particles, and the like.

  As a dosage form of the pharmaceutical composition of this embodiment, a tablet, a capsule, a powder, or a granule is preferable. Among these, as a dosage form of the pharmaceutical composition of this embodiment, a tablet is preferable and an orally disintegrating tablet is particularly preferable.

[Orally disintegrating tablets]
The orally disintegrating tablet of this embodiment includes the drug-containing particles of this embodiment described above.
The orally disintegrating tablet of this embodiment can contain an ingredient in addition to the drug-containing particles of this embodiment.
Orally disintegrating tablets are oral preparations that disintegrate rapidly in the oral cavity after being taken. Therefore, taking an unpleasant odor makes it difficult to take. As described above, since the drug-containing particles of this embodiment have a suppressed odor derived from a drug having a medoxomil group, the orally disintegrating tablet containing the drug-containing particles of this embodiment has a drug having a medoxomil group. However, the difficulty of taking due to unpleasant odor is low. Further, when the drug-containing particles of the present embodiment include a drug exhibiting a bitter taste such as olmesartan medoxomil as a drug having a medoxomil group, since the bitterness is also suppressed, the oral cavity including the drug-containing particles of the present embodiment Inwardly disintegrating tablets are less difficult to take due to bitterness.

<Drug-containing particles>
Since the details of the drug-containing particles contained in the orally disintegrating tablet of the present embodiment have been described above, the description thereof is omitted here.
The content ratio of the drug-containing particles in the orally disintegrating tablet of the present embodiment is, for example, preferably 10% by mass to 50% by mass, and 20% by mass to 40% by mass with respect to the total mass of the orally disintegrating tablet. It is more preferable that

<Formation amount>
The orally disintegrating tablet of the present embodiment can contain an externally formed component (hereinafter also simply referred to as “additive component”) with respect to the drug-containing particles. The “formation component” referred to here is a component that can contribute to the improvement of the moldability and dosing property of the tablet containing the drug-containing particles. As the pharmacologically acceptable additive for formulation, excipients, disintegrants, lubricants, binders, fluidizing agents, odor adsorbents, sweeteners, fragrances, coloring agents, etc. In the range which does not inhibit the effect of this invention, you may include. As for the additive for formulation, one component may perform two or more functions.

Examples of the excipient include the same components as those described in the section of the pharmaceutical composition.
In the orally disintegrating tablet of this embodiment, the excipient is at least one selected from D-mannitol, crystalline cellulose, lactose, erythritol, sorbitol, corn starch, and ethyl cellulose from the viewpoint of disintegrating properties of the orally disintegrating tablet. Is preferred.

  The average particle diameter of the excipient is not particularly limited, but for example, from the viewpoint of mouthfeel when taken, it is preferably 500 μm or less, more preferably 350 μm or less, and even more preferably 250 μm or less. .

Examples of the disintegrant include the same components as those of the disintegrant described in the section of the pharmaceutical composition.
In the orally disintegrating tablet of the present embodiment, the disintegrant preferably contains at least one selected from croscarmellose sodium and crospovidone from the viewpoint of disintegrating property of the orally disintegrating tablet.

Examples of the lubricant include the same components as the lubricant described in the section of the pharmaceutical composition.
In the orally disintegrating tablet of the present embodiment, the lubricant is preferably calcium stearate from the viewpoint of the productivity of the orally disintegrating tablet.

Examples of the binder include the same components as those described in the section of the pharmaceutical composition.
Examples of the fluidizing agent include the same components as the fluidizing agent described in the section of the pharmaceutical composition.

In the orally disintegrating tablet of this embodiment, the formed component preferably contains at least one selected from a magnesium salt and an aluminum salt. By including at least one selected from magnesium salts and aluminum salts in the formed component, it is possible to suppress the odor derived from the drug having a medoxomil group contained in the drug-containing particles.
Among the magnesium salts and aluminum salts, at least one selected from magnesium oxide, magnesium hydroxide, magnesium carbonate, synthetic hydrotalcite, and aluminum hydroxide is preferable from the viewpoint of odor adsorption. Examples of the aluminum hydroxide include dry aluminum hydroxide gel.

When the forming component contains at least one selected from a magnesium salt and an aluminum salt, the content of at least one selected from the magnesium salt and the aluminum salt is 1 part by mass to 10 parts by mass with respect to 100 parts by mass of the forming component. It can be a mass part.
Note that at least one selected from magnesium salts and aluminum salts may be contained in the drug-containing particles.

  Examples of sweeteners include aspartame, thaumatin, sucralose, acesulfame potassium, stevia and the like.

The orally disintegrating tablet of this embodiment may contain the formulation additive alone or in combination of two or more.
The content of the pharmaceutical additive in the formed component can be appropriately set in consideration of the content ratio of the drug-containing particles in the orally disintegrating tablet, the particle diameter of the drug-containing particles, and the like.

  When the orally disintegrating tablet of this embodiment contains olmesartan medoxomil as the drug (B) having a medoxomil group, from the viewpoint of the effectiveness of the drug, 5 mg to 40 mg of olmesartan medoxomil is used per orally disintegrating tablet. It is preferable to include.

The shape of the orally disintegrating tablet of this embodiment is not particularly limited as long as it is pharmaceutically acceptable. The shape of the orally disintegrating tablet of the present embodiment may be, for example, a round tablet or a deformed tablet, and may be appropriately set in consideration of medication compliance.
The size of the orally disintegrating tablet of this embodiment is not particularly limited as long as it is pharmaceutically acceptable. In general, in view of the fact that orally disintegrating tablets are often used for patients who have difficulty swallowing, it is preferable that the size of the orally disintegrating tablet of the present embodiment is as small as possible in consideration of medicinal effects.

The orally disintegrating tablet of this embodiment preferably has an oral disintegration time of less than 60 seconds and more preferably less than 30 seconds from the viewpoint of medication compliance.
“Oral disintegration time” in the present specification refers to the measurement of tablets measured by dropping 37 ° C. purified water at 6 mL / min into an orally disintegrating tablet using an orally disintegrating tablet measuring device. The decay time. As the orally disintegrating tablet measuring device, for example, a tricope tester (product name) manufactured by Okada Seiko Co., Ltd. can be suitably used. However, the orally disintegrating tablet measuring device is not limited to this.

The orally disintegrating tablet of this embodiment is a Japanese Pharmacopoeia dissolution test (paddle method: paddle rotation speed: 50 rpm (round per minute)) assuming drug dissolution in the small intestine, which is the drug absorption site, from the viewpoint of drug effectiveness. Hereinafter the same)), dissolution test solution: Japanese Pharmacopoeia dissolution test second solution), the dissolution rate after 30 minutes from the start of the test is preferably 20% or more, more preferably 25% or more. .
As a measuring device for the dissolution test, for example, a dissolution tester “DT-810” manufactured by JASCO Corporation can be suitably used. However, the measuring device is not limited to this.

[Method for producing orally disintegrating tablets]
The manufacturing method of the orally disintegrating tablet of this invention is not specifically limited, A well-known method can be used. The orally disintegrating tablet of the present invention can be obtained, for example, by mixing the above-mentioned drug-containing particles and an ingredient, tableting the obtained mixed powder, and drying.
The method for mixing the drug-containing particles and the formed component is not particularly limited. As a method of mixing the drug-containing particles and the forming component, for example, a known mixer such as a V-type mixer (Tsutsui Rikenki Co., Ltd.), a fluidized bed granulator (Paurec Co., Ltd.) or the like is used. The method of mixing is mentioned.
Conditions such as the time required for mixing can be appropriately adjusted depending on the types of drug-containing particles and the amount of the formed component.
The method for tableting the mixed powder of the drug-containing particles and the formed component is not particularly limited. The temperature at the time of tableting is not particularly limited, and can be set as appropriate.
Examples of the method for tableting the mixed powder of the drug-containing particles and the formed component include a rotary tableting machine (product name: HT-AP-SS, Hata Iron Works Co., Ltd.), a high-speed rotary tableting machine ( Product name: A method of tableting using a tableting machine such as AQUARIUS G, Kikusui Seisakusho).
The method for drying the tableted product obtained by tableting the mixed powder is not particularly limited. Examples of the method for drying the tableted product obtained by tableting the mixed powder include a method of drying by vacuum drying, fluidized bed drying or the like.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples unless it exceeds the gist thereof.

[Production of drug-containing particles]
<Example 1: Melt granulation>
Olmesartan medoxomil (average particle size: 7.80 μm) 100 g, Kollidon (registered trademark) CL-F (trade name, Crospovidone, manufactured by BASF) 19 g as a disintegrant, Surf Hope (registered trademark) SE PHARMA J-1803F ( Product name, sucrose stearate, HLB value: about 3 (catalog value), melting point: 60.5 ° C., carbon number of aliphatic hydrocarbon chain: 18, 49 g of Mitsubishi Chemical Foods Co., Ltd. Thereafter, they were mixed in a plastic bag and divided into 4 portions of 42 g (mixture 1).
Next, 372 g of SELFIA (registered trademark) CP-203 (trade name, crystalline cellulose (particles), spherical particles having a particle diameter of 150 μm to 300 μm, Asahi Kasei Chemicals Co., Ltd.) as core particles, a rolling fluid unit (model name: model name: MP) is set in a rolling fluidized bed granulator (model name: FD-MP-01, POWREC Co., Ltd.), and the rotor speed of the granulator is adjusted to 400 rpm and the supply air temperature is adjusted to around 80 ° C. did.
Next, 42 g of the mixture 1 was added to the granulator, and granulation for 4 minutes was repeated 4 times. After the completion of granulation, the air supply temperature was adjusted to 50 ° C. and cooled for 15 minutes to obtain a granulated product.
The obtained granulated product was sieved with a round sieve of No. 42 (355 μm) and a round sieve of No. 150 (100 μm) to obtain drug-containing particles.

<Comparative Example 1: Jet fluidized bed granulation>
400 g of SELPHYR (registered trademark) CP-203 (trade name, crystalline cellulose (particles), spherical particles having a particle diameter of 150 μm to 300 μm, Asahi Kasei Chemicals Co., Ltd.) as a core particle, a fine particle coating apparatus / Worster unit (model name: SPC) was set in a rolling fluidized bed granulator (model name: FD-MP-01, Pauleck Co., Ltd.).
Then, the supply temperature of the granulator was adjusted to 60 ° C., and 883.4 g of the coating layer (1) spray liquid having the following composition prepared in advance was sprayed into the rolling fluidized bed granulator. After spraying, the air supply temperature was adjusted to 80 ° C. and dried for 15 minutes to obtain a granulated product.
The obtained granulated product was sieved with a round sieve of No. 42 (355 μm) and a round sieve of No. 150 (100 μm) to obtain drug-containing particles.

[Spray liquid for coating layer (1)]
Olmesartan medoxomil (average particle size: 7.80 μm) 54.0 g
・ D-mannitol 53.0g
・ Hydroxypropylcellulose 10 mass% aqueous solution 265.0 g
・ Talc 17.7g
・ Pure water 493.7g

<Comparative Example 2: Fluidized bed granulation>
Olmesartan medoxomil (average particle size: 7.80 μm) 29.7 g, Theolas (registered trademark) PH-301D (trade name, crystalline cellulose, Asahi Kasei Chemicals) 220 g, D-mannitol 29.2 g, talc 9 0.7 g was charged into a rolling fluidized bed granulator (model name: FD-MP-01, Powrec Co., Ltd.) in which a fluidized granulation unit (model name: FD) was set.
Then, the air supply temperature of the granulator was adjusted to 60 ° C. to 70 ° C., and 485.9 g of the coating layer (2) spray liquid having the following composition prepared in advance was sprayed into the rolling fluidized bed granulator. After spraying, the air supply temperature was adjusted to 80 ° C. and dried for 15 minutes to obtain a granulated product.
The obtained granulated product was sieved with a round sieve of No. 42 (355 μm) and a round sieve of No. 150 (100 μm) to obtain drug-containing particles.

[Spray liquid for coating layer (2)]
・ Hydroxypropylcellulose 10 mass% aqueous solution 145.8 g
・ Purified water 340.1g

<Comparative Example 3: Rolling fluidized bed granulation>
Serfia (registered trademark) CP-203 (trade name, crystalline cellulose (particles), spherical particles having a particle diameter of 150 μm to 300 μm, Asahi Kasei Chemicals Co., Ltd.) 500 g as core particles, 11.2 g of talc, tumbling flow unit (Model name: MP) was set in a rolling fluidized bed granulator (model name: FD-MP-01, Pauleck Co., Ltd.).
And after adjusting the rotor rotation speed of a granulator to 400 rpm and supply air temperature to 60 to 70 degreeC, respectively, and adding 44 g of olmesartan medoxomil (average particle diameter: 7.80 micrometers), the coating of the following composition prepared previously 275 g of the layer (3) spray liquid was sprayed into a rolling fluidized bed granulator. Next, spraying was interrupted, 44 g of olmesartan medoxomil (average particle size: 7.80 μm) was added to the rolling fluidized bed granulator, and then 275 g of the spray liquid for coating layer (3) having the following composition prepared in advance was transferred. Spraying into the fluidized bed granulator was repeated twice. Next, spraying was interrupted, 46.1 g of olmesartan medoxomil (average particle size: 7.80 μm) was added to the rolling fluidized bed granulator, and then the spray liquid 287 for coating layer (3) having the following composition prepared in advance was prepared. .9 g was sprayed into a tumbling fluidized bed granulator (total 178.1 g of olmesartan medoxomil was added, and a total of 112.9 g of spray liquid for the coating layer (3) was sprayed). After spraying, the air supply temperature was adjusted to 80 ° C. and dried for 15 minutes to obtain a granulated product.
The obtained granulated product was sieved with a round sieve of No. 42 (355 μm) and a round sieve of No. 150 (100 μm) to obtain drug-containing particles.

[Spray liquid for coating layer (3)]
・ Hydroxypropylcellulose 10 mass% aqueous solution 333.9 g
・ Talc 11.1g
・ Purified water 767.9g

[Evaluation 1]
(Evaluation 1-1: Measurement of diacetyl area using gas chromatography)
The drug-containing particles of Example 1 and Comparative Examples 1 to 3 were weighed so that the olmesartan medoxomil was 40 mg, and each was put into four glass bottles and sealed together with an open bottle containing saturated saline. Each sealed glass bottle was stored at 40 ° C. for 1 week. The gas in the head space of the glass bottle after storage was extracted, and the area of the peak attributed to diacetyl (diacetyl area) was measured using gas chromatography.
Measurement equipment and measurement conditions are as follows.

-Measuring equipment and measuring conditions-
Gas chromatography system: 7890A (model number, Agilent Technologies)
Headspace sampler: 7697A (model number, Agilent Technologies)
Detector: Hydrogen flame ionization detector Analytical column: DB-WAX (trade name, Agilent Technology Co., Ltd.)
Injection volume: 1.0 mL
Flow rate: 5.0 mL / min Column temperature: 50 ° C

(Evaluation 1-2: Sensory evaluation of odor)
The glass bottle after storage used for the measurement of the diacetyl area was opened, and the odor in the bottle was evaluated at a five-level level of 0-4. Evaluation was performed by five panelists, the evaluation results were averaged, and the value rounded to the first decimal place was taken as the odor score.
The evaluation criteria are as follows. Levels 0 and 1 are practically acceptable levels.
In addition, the numerical value in the parenthesis written together with the evaluation standard is a range of the diacetyl area in gas chromatography in which the correlation with the evaluation standard for sensory evaluation was confirmed.

<Evaluation criteria>
0: Odorless (less than 2)
1: Smell that can be finally detected (2 or more and less than 5)
2: Smell enough to understand what kind of odor (5 or more and less than 10)
3: Smell that can be easily detected (from 10 to less than 15)
4: Strong unpleasant odor (15 or more)

(Evaluation 1-3: Sensory evaluation of bitterness)
The drug-containing particles of Example 1 and Comparative Examples 1 to 3 were weighed so that olmesartan medoxomil was 40 mg. The total amount of the drug-containing particles weighed out was put in the mouth for 30 seconds and then spouted from the mouth, and the taste was evaluated at 6 levels of 0-5. Evaluation was performed by five panelists, the evaluation results were averaged, and the value rounded to the first decimal place was taken as the bitterness score.
The evaluation criteria are as follows. Levels 0 and 1 are practically acceptable levels.

<Evaluation criteria>
0: Tasteless 1: Slightly perceivable taste 2: Slight bitterness 3: Easily perceivable bitterness 4: Strong bitterness 5: Strong bitterness

  Table 1 shows the blending amounts and blending ratios of the components used in the production methods of Example 1 and Comparative Examples 1 to 3, and the evaluation results of the obtained drug-containing particles. Moreover, the measurement result of the diacetyl area using the gas chromatography implemented about the medicine containing particle | grains obtained by the manufacturing method of Example 1 and Comparative Examples 1-3 is shown in FIG.

In addition, "-" described in the column of each component in Table 1 indicates that the component is not blended.
Further, “(au)” in FIG. 1 is an abbreviation for arbitrary unit.

As shown in Table 1, the odor derived from olmesartan medoxomil was significantly suppressed in the drug-containing particles obtained by the melt granulation method of Example 1.
On the other hand, in the drug-containing particles obtained by the jet fluidized bed granulation method of Comparative Example 1, the fluidized bed granulation method of Comparative Example 2, and the rolling fluidized bed granulation method of Comparative Example 3, the odor derived from olmesartan medoxomil Was felt.
As can be seen from Table 1 and FIG. 1, in the drug-containing particles obtained by the melt granulation method of Example 1, the jet fluidized bed granulation method of Comparative Example 1, the fluidized bed granulation method of Comparative Example 2, and the comparison Compared with the drug-containing particles obtained by the rolling fluidized bed granulation method of Example 3, the release of diacetyl from the drug-containing particles was remarkably suppressed.

In addition, as shown in Table 1, the drug-containing particles obtained by the melt granulation method of Example 1 also significantly suppressed the bitterness derived from olmesartan medoxomil.
On the other hand, in the drug-containing particles obtained by the jet fluidized bed granulation method of Comparative Example 1, the fluidized bed granulation method of Comparative Example 2, and the rolling fluidized bed granulation method of Comparative Example 3, the melt granulation of Example 1 was performed. Compared with the drug-containing particles obtained by the granule method, the bitterness derived from olmesartan medoxomil was felt very strongly.

[Manufacture of orally disintegrating tablets]
<Example 2>
5 g of olmesartan medoxomil (average particle size: 7.80 μm) and 10 g of nonparrel (registered trademark) -108 (trade name, D-mannitol, spherical particles having a particle size of 150 μm to 250 μm, Freund Sangyo Co., Ltd.) as core particles, Kollidon (registered trademark) CL-F (trade name, Crospovidone, manufactured by BASF) 0.25 g and Ryoto (registered trademark) sugar ester S-370F (trade name, sucrose stearate, HLB value: about 3 (catalog value), melting point: 60.5 ° C. (catalog value), carbon number of aliphatic hydrocarbon chain: 18, 5 g of Mitsubishi Chemical Foods Co., Ltd., using a mantle heater (As One Co., Ltd.) The alumina mortar was adjusted to a temperature in the range of 60.5 ° C to 100.5 ° C.
The raw material charged in the mortar was stirred and granulated for about 15 minutes using a pestle to obtain a granulated product.
The obtained granulated product was sieved with a No. 42 round sieve (355 μm) and a No. 100 round sieve (150 μm) to obtain drug-containing particles.
The obtained drug-containing particles and the formed component were mixed in the ratio of the following formulation (1) to obtain a tableting powder (mixed powder). The drug-containing particles were weighed and blended in an amount of 81 mg so that 20 mg of olmesartan medoxomil was contained. In addition, the compounding amount of the forming part is about 202.5 mg.
Using the rotary tableting machine (product name: HT-AP-SS, Hata Iron Works Co., Ltd.), the obtained tableting powder (mixed powder) was crushed with a 9.0 mmφ, Sumi angle R surface, The tablet was compression-molded at a rotation speed of 20 rpm and a tableting pressure of about 10 kN to obtain an orally disintegrating tablet (tablet).

[Prescription (1)]
-Drug-containing particles 28.6 parts by mass-D-mannitol / corn starch granule 59.0 parts by mass-Ethylcellulose 3.0 parts by mass-Dry aluminum hydroxide gel 3.0 parts by mass-Crospovidone 0.8 parts by mass -Croscarmellose sodium 1.2 parts-Aspartame 2.0 parts-Calcium silicate 1.0 parts-Hydrous silicon dioxide 1.0 parts-Fragrance 0.1 parts-Calcium stearate 0.3 parts

<Example 3>
In Example 2, instead of 5 g of Ryoto® sugar ester S-370F (sucrose stearate ester, HLB value: about 3, melting point: 60.5 ° C.), P-100 (trade name, glyceryl monostearate) , HLB value: about 4.3 (catalog value), melting point: 63 ° C. to 83 ° C. (catalog value), carbon number of aliphatic hydrocarbon chain: 18, RIKEN VITAMIN Co., Ltd.) 5 g, and mortar The drug-containing particles and the orally disintegrating tablets (tablets) were obtained in the same manner as in Example 2 except that the temperature was adjusted within the range of 63 ° C to 123 ° C.

<Example 4>
In Example 2, instead of 5 g of Ryoto® sugar ester S-370F (sucrose stearate, HLB value: about 3, melting point: 60.5 ° C.), Ryoto® sugar ester S-170 (Trade name, sucrose stearate, HLB value: about 1 (catalog value), melting point: 68.3 ° C. (catalog value), carbon number of aliphatic hydrocarbon chain: 18, Mitsubishi Chemical Foods Co., Ltd.) 5 g And the drug-containing particles and orally disintegrating tablets (tablets) were obtained in the same manner as in Example 2 except that the temperature of the mortar was adjusted within the range of 68.3 ° C to 108.3 ° C. It was.

<Example 5>
In Example 2, instead of 5 g of Ryoto® sugar ester S-370F (sucrose stearate ester, HLB value: about 3, melting point: 60.5 ° C.), Labriwax®-103 (commercial product) Name, hardened rapeseed oil, HLB value: −11.5 (calculated by Davies method), melting point: 69 ° C. (catalog value), carbon number of aliphatic hydrocarbon chain: mainly 18, 5 g Freund Sangyo Co., Ltd. is used The drug-containing particles and the orally disintegrating tablets (tablets) were obtained in the same manner as in Example 2 except that the temperature of the mortar was adjusted within the range of 69 ° C to 109 ° C.

<Example 6>
In Example 2, instead of 5 g of Ryoto® sugar ester S-370F (sucrose stearate ester, HLB value: about 3, melting point: 60.5 ° C.), Steadic Acid, Powder, NF-GenAR (commercial product) Name, stearic acid, HLB value: 1.0 (calculated by the Davies method), melting point: 53 ° C. to 59 ° C. (catalog value), number of carbons of aliphatic hydrocarbon chain: 18, Avantor Performance Materials) 5 g was used. In this manner, drug-containing particles and orally disintegrating tablets (tablets) were obtained in the same manner as in Example 2 except that the temperature of the mortar was adjusted within the range of 53 ° C to 99 ° C.

<Example 7>
In Example 2, instead of 5 g of Ryoto® sugar ester S-370F (sucrose stearate ester, HLB value: about 3, melting point: 60.5 ° C.), polishing wax-105 (trade name, Carnauba wax, HLB value: -16.7 (calculated by Davies method), melting point: 80 ° C. to 86 ° C. (catalog value), carbon number of aliphatic hydrocarbon chain: 24 to 28, 5 g of Freund Sangyo Co., Ltd. was used And the drug containing particle | grains and the orally disintegrating tablet (tablet) were obtained like Example 2 except having adjusted the temperature of the mortar in the range of 80 to 126 degreeC.

<Example 8>
In Example 2, instead of 5 g of Ryoto® sugar ester S-370F (sucrose stearate ester, HLB value: about 3, melting point: 60.5 ° C.), NIKKOL® deodorized stearyl alcohol (commercial product) Name, stearyl alcohol, HLB value: 0.8 (calculated by the Davies method), melting point: 59 ° C. to 60 ° C. (catalog value), aliphatic hydrocarbon chain carbon number: 18, Nikko Chemicals Co., Ltd. 5 g The drug-containing particles and the orally disintegrating tablets (tablets) were obtained in the same manner as in Example 2 except that the temperature of the mortar was adjusted within the range of 59 ° C to 100 ° C.

<Example 9>
In Example 2, instead of 5 g of Ryoto® sugar ester S-370F (sucrose stearate, HLB value: about 3, melting point: 60.5 ° C.), Ryoto® sugar ester S-070 (Product name, sucrose stearate ester, HLB value: about 0, melting point: 65.7 ° C. (catalog value), carbon number of aliphatic hydrocarbon chain: 18, Mitsubishi Chemical Foods Co., Ltd.) And the drug containing particle | grains and the orally disintegrating tablet (tablet) were obtained like Example 2 except having adjusted the temperature of the mortar in the range of 65.7 degreeC-105.7 degreeC.

<Comparative example 4>
In Example 2, instead of 5 g of Ryoto® sugar ester S-370F (sucrose stearate, HLB value: about 3, melting point: 60.5 ° C.), Ryoto® sugar ester S-770 (Product name, sucrose stearate, HLB value: about 7 (catalog value), melting point: 62.4 ° C. (catalog value), carbon number of aliphatic hydrocarbon chain: 18, Mitsubishi Chemical Foods Co., Ltd.) 5 g And drug-containing particles and orally disintegrating tablets (tablets) were obtained in the same manner as in Example 2 except that the temperature of the mortar was adjusted to the range of 62.4 ° C to 102.4 ° C. It was.

<Comparative Example 5>
In Example 2, instead of 5 g of Ryoto® sugar ester S-370F (sucrose stearate, HLB value: about 3, melting point: 60.5 ° C.), Ryoto® sugar ester S-1170F (Trade name, sucrose stearate, HLB value: about 11 (catalog value), melting point: 60.9 ° C. (catalog value), number of carbons of aliphatic hydrocarbon chain: 18, Mitsubishi Chemical Foods Co., Ltd.) 5 g The drug-containing particles and the orally disintegrating tablet (tablet) were obtained in the same manner as in Example 2 except that the temperature of the mortar was adjusted within the range of 60.9 ° C to 100.9 ° C. It was.

<Comparative Example 6>
In Example 2, instead of 5 g of Ryoto® sugar ester S-370F (sucrose stearate, HLB value: about 3, melting point: 60.5 ° C.), Ryoto® sugar ester S-1670 (Product name, sucrose stearate, HLB value: about 16 (catalog value), melting point: 60.7 ° C. (catalog value), number of carbons of aliphatic hydrocarbon chain: 18, Mitsubishi Chemical Foods Co., Ltd.) 5 g The drug-containing particles and the orally disintegrating tablets (tablets) were obtained in the same manner as in Example 2 except that the temperature of the mortar was adjusted within the range of 60.7 ° C to 100.7 ° C. It was.

<Comparative Example 7>
In Example 2, instead of 5 g of Ryoto® sugar ester S-370F (sucrose stearate ester, HLB value: about 3 (catalog value), melting point: 60.5 ° C.), macrogol 6000 (powder) (Product name, Macrogol 6000, HLB value: about 19 (catalog value), melting point: 55 ° C. to 60 ° C. (catalog value), Sanyo Chemical Co., Ltd.) 5 g, and mortar temperature of 55 ° C. to A drug-containing particle and an orally disintegrating tablet (tablet) were obtained in the same manner as in Example 2 except that the temperature was adjusted within the range of 100 ° C.

<Example 10>
Olmesartan medoxomil (average particle size: 7.80 μm) 100 g, Kollidon (registered trademark) CL-F (trade name, Crospovidone, manufactured by BASF) 19 g as a disintegrant, Surf Hope (registered trademark) SE PHARMA J-1803F ( Product name, sucrose stearate, HLB value: about 3 (catalog value), melting point: 60.5 ° C., carbon number of aliphatic hydrocarbon chain: 18, 49 g of Mitsubishi Chemical Foods Co., Ltd. Thereafter, they were mixed in a plastic bag and divided into 4 portions of 42 g (mixture 1).
Next, 372 g of Nonparel (registered trademark) -108 (trade name, D-mannitol, spherical particles having a particle diameter of 150 μm to 250 μm, Freund Sangyo Co., Ltd.) as a core particle, a rolling fluid unit (model name: MP) The set rolling fluidized bed granulator (model name: FD-MP-01, Paulek Co., Ltd.) was charged, and the rotor rotation speed of the granulator was adjusted to 400 rpm and the supply air temperature was adjusted to around 80 ° C.
Next, 42 g of the mixture 1 was added to the granulator, and granulation for 4 minutes was repeated 4 times. After the completion of granulation, the air supply temperature was adjusted to 50 ° C. and cooled for 15 minutes to obtain a granulated product.
The obtained granulated product was sieved with a round sieve of No. 42 (355 μm) and a round sieve of No. 150 (100 μm) to obtain drug-containing particles.

The obtained drug-containing particles and the component to be formed were mixed in the ratio of the above formula (1) to obtain a tableting powder (mixed powder). The drug-containing particles were weighed and blended to contain 20 mg of olmesartan medoxomil.
Using the rotary tableting machine (product name: HT-AP-SS, Hata Iron Works Co., Ltd.), the obtained tableting powder (mixed powder) was used, using a 9.5 mmφ, Sumi angle R surface punch, The tablet was compression-molded at a rotation speed of 20 rpm and a tableting pressure of about 10 kN to obtain an orally disintegrating tablet (tablet).

<Example 11>
In Example 10, instead of 372 g of nonparel (registered trademark) -108 (D-mannitol, spherical particles having a particle diameter of 150 μm to 250 μm) as core particles, SELPHYR (registered trademark) CP-203 (crystalline cellulose (particles), Drug-containing particles and orally disintegrating tablets (tablets) were obtained in the same manner as in Example 10 except that 372 g of spherical particles having a particle diameter of 150 μm to 300 μm were used.

<Example 12>
Drug-containing particles and orally disintegrating tablets (tablets) were obtained in the same manner as in Example 10, except that the amount of Kollidon (registered trademark) CL-F (crospovidone) was changed from 19 g to 38 g.

<Example 13>
In Example 10, instead of 19 g of Kollidon (registered trademark) CL-F (crospovidone) as a disintegrant, 19 g of ECG505 (trade name, carmellose calcium, manufactured by Gotoku Pharmaceutical Co., Ltd.) was used. In the same manner as in Example 10, drug-containing particles and orally disintegrating tablets (tablets) were obtained.

<Example 14>
In Example 10, drug-containing particles and orally disintegrating tablets (tablets) were obtained in the same manner as in Example 10 except that the disintegrant was not used.

[Evaluation 2]
(Evaluation 2-1: Dissolution test)
About the orally disintegrating tablet of Examples 2-14 and Comparative Examples 4-7, the dissolution test was done according to the dissolution test as described in the 16th revision Japanese Pharmacopoeia second supplement "Olmesartan medoxomil tablet". The dissolution test was performed by a paddle method (paddle rotation speed: 50 rpm) using a dissolution tester “DT-810” manufactured by JASCO Corporation. As the dissolution test solution, Japanese Pharmacopoeia dissolution test second solution (volume: 900 mL) was used, and the temperature was maintained at 37 ± 0.5 ° C. after heating and degassing at 50 ° C. for 2 hours or more.
The amount of olmesartan medoxomil released from the tablet at a test time of 30 minutes was measured at a wavelength of 257 nm using an ultraviolet spectrophotometer, and the dissolution rate (%) was calculated.

(Evaluation 2-2: Measurement of diacetyl area using gas chromatography)
The orally disintegrating tablets of Examples 2 to 14 and Comparative Examples 4 to 7 were put in 17 glass bottles together with open bottles containing saturated saline and sealed. Each sealed glass bottle was stored at 40 ° C. for 1 week. The gas in the head space of the glass bottle after storage was extracted, and the area of the peak attributed to diacetyl (diacetyl area) was measured using gas chromatography.
Measurement equipment and measurement conditions are as follows.

-Measuring equipment and measuring conditions-
Gas chromatography system: 7890A (model number, Agilent Technologies)
Headspace sampler: 7697A (model number, Agilent Technologies)
Detector: Hydrogen flame ionization detector Analytical column: DB-WAX (trade name, Agilent Technology Co., Ltd.)
Injection volume: 1.0 mL
Flow rate: 5.0 mL / min Column temperature: 50 ° C

(Evaluation 2-3: Sensory evaluation of odor)
The glass bottle after storage used for the measurement of the diacetyl area was opened, and the odor in the bottle was evaluated at a five-level level of 0-4. Evaluation was performed by five panelists, the evaluation results were averaged, and the value rounded to the first decimal place was taken as the odor score.
The evaluation criteria are as follows. Levels 0 and 1 are practically acceptable levels.
In addition, the numerical value in the parenthesis written together with the evaluation standard is a range of the diacetyl area in gas chromatography in which the correlation with the evaluation standard for sensory evaluation was confirmed.

<Evaluation criteria>
0: Odorless (less than 2)
1: Smell that can be finally detected (2 or more and less than 5)
2: Smell enough to understand what kind of odor (5 or more and less than 10)
3: Smell that can be easily detected (from 10 to less than 15)
4: Strong unpleasant odor (15 or more)

(Evaluation 2-4: Sensory evaluation of bitterness)
About each of the orally disintegrating tablet of Examples 2-14 and Comparative Examples 4-7, after putting it in the mouth for 30 seconds, it discharged, and the taste was evaluated in the six-step level of 0-5. In addition, the orally disintegrating tablets of Examples 2 to 14 and Comparative Examples 4 to 7 are included in the mouth for 30 seconds, so that the tablets disintegrate. Evaluation was performed by five panelists, the evaluation results were averaged, and the value rounded to the first decimal place was taken as the bitterness score.
The evaluation criteria are as follows. Levels 0 and 1 are practically acceptable levels.

<Evaluation criteria>
0: Tasteless 1: Slightly perceivable taste 2: Slight bitterness 3: Easily perceivable bitterness 4: Strong bitterness 5: Strong bitterness

Tables 2 and 3 show the content (unit: mg) of each component per drug-containing particle tablet obtained by the production methods of Examples 2 to 14 and Comparative Examples 4 to 7, and the evaluation results.
In addition, "-" described in the column of each component in Table 2 and Table 3 indicates that the component is not contained.

As shown in Table 2 and Table 3, in the orally disintegrating tablets of Examples 2 to 14, the odor derived from olmesartan medoxomil was suppressed.
On the other hand, in the orally disintegrating tablets of Comparative Examples 4 to 7, an odor derived from olmesartan medoxomil was felt.
As can be seen from Tables 2 and 3, the orally disintegrating tablets of Examples 2 to 14 significantly suppressed the release of diacetyl from the orally disintegrating tablets as compared with the orally disintegrating tablets of Comparative Examples 4 to 7. It had been.

Moreover, as shown in Table 2 and Table 3, the orally disintegrating tablets of Examples 2 to 14 were also significantly suppressed in bitterness derived from olmesartan medoxomil.
On the other hand, the orally disintegrating tablets of Comparative Examples 4 to 7 strongly felt the bitterness derived from olmesartan medoxomil compared to the orally disintegrating tablets of Examples 2 to 14.

The orally disintegrating tablets of Examples 2 to 4 containing at least one selected from glyceryl monostearate and sucrose stearate as compound (C) in the coating layer of drug-containing particles Compared with the orally disintegrating tablet, the dissolution property of olmesartan medoxomil was excellent.
The orally disintegrating tablets of Examples 10 to 13 containing the disintegrant (D) in the coating layer of the drug-containing particles do not contain the disintegrant (D) for the odor and bitterness derived from olmesartan medoxomil. However, the dissolution property of olmesartan medoxomil was superior to the orally disintegrating tablet of Example 14 containing no disintegrant (D).

Claims (10)

Nuclear particles (A),
Drug (B) coated with core particles (A) and having a medoxomil group, and an aliphatic hydrocarbon chain having a melting point of 50 to 100 ° C., an HLB value of 6 or less, and a carbon number of 12 or more A coating layer comprising a compound (C) having
A method for producing drug-containing particles, comprising a melt granulation step for obtaining drug-containing particles having the above by melt granulation.   In the melt granulation step, at least the core particles (A), the drug (B) having a medoxomil group, and the compound (C) -containing component are heated to the melting point of the compound (C) or higher, and the rolling means and stirring are performed. The production method according to claim 1, wherein granulation is performed using at least one means selected from the means.   The manufacturing method of Claim 1 or Claim 2 in which a core particle (A) contains at least 1 sort (s) chosen from D-mannitol and crystalline cellulose.   The method according to any one of claims 1 to 3, wherein the drug (B) having a medoxomil group has an average particle size of 20 µm or less.   The manufacturing method of any one of Claims 1-4 in which a coating layer further contains a disintegrating agent (D).   The production method according to claim 5, wherein the disintegrant (D) contains at least one selected from crospovidone and carmellose calcium.   The production method according to any one of claims 1 to 6, wherein the compound (C) is at least one selected from a glycerin fatty acid ester and a sucrose fatty acid ester.   The production method according to any one of claims 1 to 7, wherein the compound (C) is at least one selected from glyceryl monostearate and sucrose stearate.   The production method according to any one of claims 1 to 8, wherein the drug (B) having a medoxomil group is olmesartan medoxomil.   10. The melt granulation step according to claim 1, wherein 20 to 150 parts by mass of the compound (C) is used with respect to 100 parts by mass of the drug (B) having a medoxomil group. Production method.